1. Field of the Invention
The present invention relates generally to the field of pharmaceutics, polymer chemistry, and medicine. More particularly, it concerns pH-sensitive hydrogels that may be used to deliver a therapeutic protein to a subject.
2. Description of Related Art
Protein therapy offers a number of advantages in disease treatment that cannot be matched by traditional therapy with small molecule drugs. The complexity of macromolecules can afford protein therapeutics high specificity to their target that prevents widespread systemic side effects, yielding well-tolerated, highly active, and effective treatment options for a variety of diseases (Leader et al., 2008). Because of these benefits, protein-based drugs have remained one of the most common classes of newly FDA-approved drugs in recent years, accounting for 23% of new drugs in 2012 (Mullard, 2013) and 20% of new drugs in 2011 (U.S. Food and Drug Administration, 2012). Since recombinant insulin was first approved in 1982, the field has expanded to over 150 different FDA-approved protein therapeutics that accounted for $108 billion in sales in 2010 (Dimitrov, 2012).
Unfortunately, therapeutic proteins are primarily administered via injection only. Because protein therapeutics most frequently require repeated administrations, the cumulative frustration with a painful and inconvenient administration method often causes patients to intentionally skip injections, leading to less effective treatment (Peyrot et al., 2010). Oral delivery is a more desirable route of administration due to its ease, familiarity, and avoidance of chronic irritation (as experienced with injection or intranasal delivery methods). Additionally, oral delivery often offers lower cost, as orally-delivered drugs need not be produced in the highly sterile cleanroom environments required for injectables (Salama et al., 2006). Development of an oral delivery strategy for protein therapeutics would therefore be a boon to both patients and the protein therapeutics industry by offering improved patient quality of life and reduced cost.
Despite significant interest, the oral route has not yet been widely adopted with protein-based drugs because of the human body's natural mechanisms for breaking down ingested protein into substituent amino acids. The drug must first retain its structure and integrity through the highly acidic and proteolytic environment of the stomach, in which it spends an average time of around 3.5 hours (Dressman and Kramer, 2005). The drug then passes on to the small intestine, where it must remain stable in neutral conditions (pH 6.8-7.4), survive attack from additional proteolytic enzymes, pass through the mucosal lining, and cross the epithelial cell layer by either paracellular transport through the tight junctions or transcellular transport through the cells. The drug then enters the bloodstream, where it will be distributed throughout the body to perform its function. Because of this series of barriers, protein therapeutics exhibit extremely low bioavailability via the oral route without some means of protection (Morishita and Peppas, 2006; Renukuntla et al., 2013; Gupta et al., 2013).
Studies seeking to overcome these delivery barriers using pH-responsive hydrogels such as poly(methacrylic acid-grafted-poly(ethylene glycol)) (P(MAA-g-EG)) or poly(methacrylic acid-co-N-vinylpyrrolidone) (P(MAA-co-NVP) to deliver proteins such as insulin and human growth hormone have been relatively successful, but still suffer from low bioavailability compared to injection, resulting in wasted drug and therefore higher cost (Lowman et al., 1999; Can et al., 2010; Can and Peppas, 2010; Foss and Peppas, 2004; Kamei et al., 2009; Kavimandan et al., 2006). Additionally, studies seeking to deliver proteins exhibiting high isoelectric points (pI) have been hampered by coulombic interactions in the small intestine between the anionic hydrogel and cationic protein, resulting in binding rather than release for uptake into the bloodstream (Can et al., 2010). Clearly, there exists a need for improved methods of oral delivery of therapeutic proteins.